CZ303112B6 - Process for preparing sulfonamides - Google Patents

Abstract

In the present invention, there is disclosed a process for the preparation of a sulfonamide of the general formula II, comprising reacting at a temperature ranging from 30 to 160 degC an aniline of the general formula I, with a sulfonating agent A of the general formula Re1-SOi2-Z in the presence of a catalytic amount of either: (i) an amide B-1, other than N,N-dimethylformamide, or (ii) a boiling tertiary amine B-2 having boiling point at atmospheric pressure higher than 140 degC with the proviso that if the B-1 amide is N,N-dimethylformamide the reaction takes place at a temperature ranging from 120 to 140 degC and the meanings of the groups X, Y, Z, R and Re1 are as defined in the descriptive section.

Description

(57)

A process for the preparation of sulfonamides of formula II which comprises reacting an aniline of formula 1 with a sulfonating agent A of formula R 1 SCU-Z at a temperature in the range of 30 to 160 ° C in the presence of a catalytic amount of either (i) amide B1 or (ii) a tertiary amine B-2 boiling at atmospheric pressure greater than 140 ° C, provided that when the amide Β-1 is N, Ndm ethyl formamide, the reaction proceeds at a temperature of 120 to 140 ° C, the meaning of the groups X, Y, Z, R, and R ¹ are defined in the specification.

Z 303112 B6

Process for preparing sulfonamides

Technical field

The present invention relates generally to a process for the preparation of sulfonamides. In particular, the invention relates to a process for preparing N- (substituted phenyl) sulfonamides from suitable aniline derivatives. More specifically, the present invention relates to the reaction of anilines with a sulfonating agent in the presence of a catalyst to form N- (substituted phenyl) sulfonamides.

BACKGROUND OF THE INVENTION

It is known that some N- (substituted phenyl) sulfonamides may exhibit pesticidal effects and that such compounds are useful for the preparation of some pesticides. For example, the use of N- [2,4-dichloro-5- [4- (difluoromethyl) -4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl] Phenylmethane sulfonamide as a herbicide is described in U.S. Patent 4,818,275 (FMC Corporation, issued April 4, 1989). According to U.S. Pat. No. 4,818,275, N- [2,4-dichloro-5- [4- (difluoromethyl) -4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl] -phenyl] -methanesulfonamide is prepared by reacting the corresponding arylamine with methanesulfonyl chloride and an excess of triethylamine in dichloromethane, followed by reaction of the resulting bis (methanesulfonyl) amine intermediate with sodium hydroxide. Furthermore, it is also known that N- (substituted aryl) sulfonamides can be prepared directly by reacting arylamine with methanesulfonyl chloride. However, in order to complete this reaction, an acceptor or scavenger of hydrochloric acid such as pyridine or triethylamine must be added to the reaction mixture in excess. If such reactions are carried out on a large scale, they must be part of such a process for the isolation and recycling or disposal of said hydrochloric acid scavenger. This isolation and recycling / disposal results in a significant increase in production costs. Another adverse factor in attempts to convert arylamine to N- (substituted aryl) sulfonamides is the low yield of the desired product, due to the formation of a by-product, bis (methanesulfonyl) amine, which is formed in an attempt to complete the reaction to completion. Accordingly, there is a need for a process for the preparation of N (substituted aryl) sulfonamides directly from arylamine, in which no acid scavenger is added to the reaction mixture and which does not substantially generate the bis (methanesulfonyl) amine by-product.

The essence of the inventions

It is an object of the present invention to provide sulfonamides from highly concentrated (> 50 percent) anilines in the presence of a catalyst that does not employ acid scavengers and does not substantially generate the cis (methanesulfonyl) amine by-product.

Accordingly, the present invention provides a process for preparing sulfonamides of formula II

- 1 GB 303112 B6

Y

R

HN

AND

(TI) 2 _, characterized in that it comprises at least the reaction of the aniline of the formula (1)

Η ^ Ν

X

Y

R (I) with a sulfonating agent A of the formula R 1 -SO ₂ -Z at a temperature ranging from 30 to 160 ° C in the presence of a catalytic amount of either (i) amide B1 or (ii) tertiary amine B- 2 having a boiling point at atmospheric pressure above 140 ° C, provided that when the amide B1 is Ν, Ν-dimethyl formamide, the reaction is carried out at a temperature in the range of from 120 to 160 ° C, the groups X and Y in both formulas 1 and II and Z are independently selected from the group consisting of hydrogen, halogen, C _{μ2 ο} alkyl, C | _ ₂ of haloalkyl, amino, nitro, C .. _{2 O} alkoxy group, a hydroxyl group, an anhydride group, a C ₂ alkylthio, C ₅ | ₀ arylthio, C ₅ _ _[0 aryloxy group, a C] _ about ₃ alkylsulfonyl, C ₅ _io aryl sulphonyl group and a substituted or unsubstituted C5-10 aryl group, wherein said C ₅ _ ₁₀ aryl group may be substituted with one or more substituents selected from the group consisting of halogen, C | _2o alkyl, C1-20 alkoxy, nitro, amino, amido CY20 alkylthio, C ₅ _i ₀ aryl group, a C _{5 _) 0} arylthio, C ₅ _ | _O aryloxy, C _1-2 alkylsulfonyl and C 5-10 arylsulfonyl;

group R in both formulas I and 11 is independently selected from the group consisting of hydrogen, C | - ₂₀ alkyl, C] _ ₂ a haloalkyl group, a C ₅ _i ₀ aryloxy group, a substituted or unsubstituted C ₅ aryl _i ₀ and a substituted or unsubstituted 5 to membered heterocyclyl group containing 1 to 4 atoms selected from nitrogen, sulfur and oxygen wherein said C ₅ _i ₀ aryl or 5 to membered heterocyclyl group may be substituted by one or more substituents selected from the group consisting of halogen, C] _ ₂₀ alkyl, C | _ ₂₀ alkoxy, nitro, amino, amido, C ₂₀ alkylthio, C ₅ _i ₀ aryl, CA 10 arylthio, C ₅ _io aryloxy passthroughs alkylsulfonyl and C _{5 10} arylsulfonyl ; and R ¹ is selected from the group consisting of hydrogen, C] _2q alkyl, C | _ ₂₀ haloalkyl group, a C ₅ _io aryl group.

-2GB 303112 B6

Preferred suifonamides prepared according to the present invention are those in which both X and Y are halogen; R represents a substituted or unsubstituted heterocyclyl group which may be substituted by one or more substituents selected from the group consisting of halogen, alkyl of 1 to 20 carbon atoms, alkoxy of 1 to 20 carbon atoms, nitro, amino, amido, alkylthio, aryloxy, aryl, arylthio, alkylsulfonyl, and arylsulfonyl; and R ¹ represents an aryl group or an alkyl group.

Particularly preferred sulfonamides prepared according to the present invention are those sulfonamides wherein both X and Y are chlorine or fluorine; R is 4-difluoromethyl-1,4,5-dihydro-3-methyl-5-oxo-1 H -1,2,4-triazol-1-yl; 1-methyl 1-6-trifluoromethyl-1-2 A 4- (1H, 3H) -pyrimidindion-3-yl group or a 1-amino-6-trifluoromethyl-2,4- (1H, 3H) -pyrimidindion-3-yl group; and R ¹ is methyl. Even more preferred suifonamides prepared according to the present invention are those in which X is 2-chloro or 2-fluoro and Y is 4-chloro; R is 4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-2,4,4-triazol-1-yl; and R ¹ is methyl.

Preferred anilines which can be used according to the invention are anilines in which both X and Y are halogen atoms; R represents a substituted or unsubstituted heterocyclyl group which may be a substituted heterocyclyl group which may be substituted by one or more substituents selected from a halogen atom, an alkyl group containing from 1 to 20 carbon atoms, an alkoxy group containing from 1 to 20 carbon atoms, nitro, amino, amido. alkylthio, aryloxy, aryl, arylthio, alkylsulfonyl, and arylsulfonyl.

Particularly preferred anilines which can be used according to the invention are those in which X and Y are both chlorine or fluorine; R is 4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-2,4,4-triazol-1-yl, 1-methyl-6-trifluoromethyl-2,4- (1H 3H) -pyrimidindion-3-yl or 1-amino-6-trifluoromethyl-2,4- (1H, 3H) -pyrimidindion-3-yl. Even more preferred anilines which can be used in the present invention are those in which X is 2-chloro or 2-fluoro and Y is 4-chloro; and R is 4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-2,4,4-triazol-1-yl. Preferred sulfonating agents A. which can be used in the present invention are compounds which allow the sulfonyl group to be attached to the amino group. Examples of sulfonating agents A that can be used in the present invention include, but are not limited to, compounds of formula R-SO 2 -Z, wherein R and Z are as defined above. Preferred sulfonating agents A which can be used according to the invention are compounds of the formula R ¹ SO ² -Z in which R 1 is an aryl or alkyl group and Z is a halogen atom or an anhydride group. Particularly preferred sulfonating agents A which may be used in the present invention are compounds of the formula R 1 -SO 2 -Z, wherein R ¹ is an alkyl group and Z is a halogen atom. An even more preferred sulfonating agent A which can be used in the present invention is a compound of formula R-SO 2 -Z, wherein R ¹ is methyl and Z is chloro.

The term "catalytic amount" as used herein refers to an amount of high boiling amide B1 or tertiary amine B-2 which, when added to the reaction mixture, causes the reaction to proceed more rapidly, but said amide Β-1 or tertiary amine B-2. high boiling point is not subject to permanent chemical change.

-3GB 303112 B6

Suitable amides B-1 and high boiling tertiary amines B-2 which can be used according to the invention are those amides or amines which are capable of forming an activated complex with the aniline of the formula I. Amides B-1 or amines B-2 which can be used in the present invention include, but are not limited to, pyrrolidinones, ureas, acetamides, phosphoramides, isoquinolines, and triazoles. A group of preferred amides B1 or amines B-2 which can be used according to the invention include 1-methyl-2-pyrrolidinone (also referred to hereinafter as NMP), 1,1,3,3-tetramethylurea, N, Nd-methylacetamide (also abbreviated as DMAC), hexamethylphosphoramide (also abbreviated as HMPA), isoquinoline and 1- (2,4-dichloro-5-acetamidophenyl) -4-difluoroinctyl-4 5-dihydro-3-methyl-1H-1,2,4-triazol-5-one (also referred to hereinafter as 5-N-acetyl).

Said reaction is preferably carried out at an elevated temperature, such as a temperature in the range of about 110 to about 160 ° C, more preferably in the range of about 120 to about 150 ° C, preferably for a time period of about 3 hours to about 12 hours, more preferably for from about 3 hours to about 7 hours. The reaction may be carried out at lower temperatures, but in this case a longer time is usually required to complete the reaction. In addition, the reaction can be carried out at atmospheric or elevated pressure.

The reactions of the present invention can be carried out by mixing aniline of formula I with about 1 to about 5 molar equivalents, preferably about 1.3 to about 4 molar equivalents of sulfonating agent A relative to the aniline of formula I and a catalytic amount which may be, for example, from about 0.001 to about 1 molar equivalent, preferably from about 0.001 to about 0.06 molar equivalent of high temperature amide B1 or tertiary amine B-2 relative to the aniline of formula (I).

In addition, the reaction of the present invention can be carried out in the absence or presence of a solvent. Suitable solvents for use in the present invention are those which at elevated temperature make it possible to form a miscible mixture with the aniline of Formula I. Solvents which can be used in the present invention include, but are not limited to, aromatic, aican, or alkene solvents. to these examples. Preferred solvents for use herein include toluene, xylene, and diethylbenzene. A particularly preferred solvent for use in the present invention is toluene.

In another embodiment of the present invention, a sulfonamide of formula II wherein X, Y, R and R 'are as defined above is prepared by reacting a suitable aniline of formula I with sulfonating agent A of formula R 2 SO 4 -Z, wherein the groups R ¹ and Z are as defined above, and N, Nd and methyl formamide (which is hereinafter also referred abbreviated to DMF), wherein said reaction is performed for from about 3 hours to about 7 hours, preferably for about 4 hours to about 7 hours and at a temperature in the range of about 120 to about 160 ° C, preferably in the range of about 125 to about 150 ° C.

Using DMF, the reaction of the invention can be carried out under conditions wherein the molar ratio of sulfonating agent A to aniline of formula I is in the range of about 1.5 to about 6, preferably about 1.5 to about 4, and the molar ratio of DMF to The aniline of formula I is in the range of about 0.001 to about 0.09, preferably about 0.001 to about 0.05. The sulfonating agents A described above can also be used in combination with DMF. A preferred sulfonating agent A that can be used in combination with DMF is that sulfonating agent A wherein R ¹ is methyl and Z is chloro.

Similarly to the above, the reaction of the present invention using DMF can be carried out at atmospheric or elevated pressure. Further, the DMF reaction may be carried out in the absence or presence of a suitable solvent, from above

The solvents described can also be used in combination with DMF. Preferred solvents that can be used in combination with DMF include toluene, xylene, and diethyl benzene.

The preferred and particularly preferred sulfonamides of formula II and / or anilines of formula I described above may also be prepared and / or used in combination with DMF.

The methods of the present invention are safer and more cost effective than the prior art methods because they do not employ an acceptor or a hydrochloric acid scavenger, the catalysts used are safer and the time required to complete the reaction is shorter. A further advantage of the methods of the invention is that usually more than 90 percent, often more than 95 percent of the starting aniline is converted to the sulfonamide of formula (II).

Unless otherwise indicated, the terms "alkyl", "alkoxy", "aryloxy" and "alkoxy aryl" are used herein, either alone or as part of a compound indicating a larger group , linear or branched chains containing at least one or two carbon atoms and preferably up to 20 carbon atoms, more preferably up to 10 carbon atoms and most preferably up to 7 carbon atoms.

The term "halogen atom" or "halo" as used herein means, unless otherwise indicated, a fluorine atom, a bromine atom, an iodine atom or a chlorine atom.

The term "aryl" or "aryl group" as used herein means, unless otherwise indicated, an aromatic ring structure containing from 5 to 10 carbon atoms.

The term "heteroaryl" or "heteroaryl" as used herein means, unless otherwise indicated, an aromatic ring structure containing from 1 to 4 nitrogen, sulfur or oxygen atoms or a combination thereof, the remaining atoms of said aromatic ring structure being carbon atoms.

The term "high boiling point" as used herein, unless otherwise indicated, refers to compounds whose boiling point at atmospheric pressure is greater than 140 ° C.

The term "room temperature" as used herein means, unless otherwise indicated, a temperature not exceeding 30 ° C.

The term "elevated temperature" as used herein means, unless otherwise indicated, a temperature higher than about room temperature, such as, for example, a temperature in the range of about 10 ° C to about 160 ° C.

J '' Γ 'i * ¹ *

DETAILED DESCRIPTION OF THE INVENTION

The present invention will now be described in more detail by means of the following examples, which, however, are to be construed as merely illustrative and not limiting of the invention.

Example 1

This example describes a process for preparing N- [2,4-dichloro-5- [4- (difluoromethyl) -4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl] phenyl methanesulfonamide using NMP as a catalyst.

A solution of 20.0 grams (0.054 mol - 1.0 equivalent) of 1- (5-amino-2,4-dichlorophenyl) -4,5-dihydro-4-difluoromethyl-3-methyl-1,2,4-triazole-5 ( 1 H) -one having a purity of 83.1 percent, 9.2 grams (0.08 moles of 1.5 equivalents) of methanesulfonyl chloride, 0.17 grams (0.002 moles - 0.04 equivalents) of NMP

And 17 grams of toluene (the excess weight of triazole relative to the solvent was 18 percent) was heated to 110 ° C under nitrogen for 6 hours with stirring.

Example 2

This example describes a process for preparing N- [2,4-dichloro-5- [4- (difluoromethyl) -4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl] phenyl] methanesulfonamide using DMF as a catalyst.

io

Into a round-bottomed flask equipped with a mechanical stirrer and a thermometer was placed 104.5 grams (0.3 mol - 1.0 equivalent) of M5-amino-2,4-dichlorophenyl) -4,5-dihydro-4-difluoromethyl-3- Methyl-1,2,4'-triazol-5 (1H) -one having a purity of 88.7 percent, 52.6 g (0.45 mol 1.5 equivalents) of methanesulfonyl chloride, 0.9 g (0.012 mol - 0), DMF is and 93 grams of toluene (the excess weight of triazole relative to toluene was 12 percent). After all the components were added, the reaction mixture was heated to about 148 ° C for 4 hours. The reaction mixture was then cooled to 95 ° C and an additional 569 grams of toluene was added (the triazole content of the total amount of toluene was 15.8 percent). Subsequently, the reaction mixture was allowed to cool to room temperature and stirred for an additional 18 hours. After this time, the reaction mixture was heated to 60 ° C and transferred to a second one-liter round bottom flask, also equipped with a mechanical stirrer and thermometer. After the mixture had been transferred, it was heated to 85 ° C and 490 ml of water at 0 ° C was added. The resulting mixture was stirred and heated to 85 ° C for 30 minutes. The organic layer was separated from aqueous and an additional 490 mL of 85 ° C water was added. The resulting mixture was stirred again and heated to 85 ° C for 30 minutes. The organic layer was separated from the aqueous layer, allowed to cool to room temperature and stirred for about 48 hours. After this time, the reaction mixture was heated to 90 ° C to dissolve the solids, cooled to 85 ° C, and stirred at this temperature for 30 minutes. The reaction mixture was then allowed to cool to 20 ° C over a period of 8 hours, with a cooling rate of 30 l and 5 ° C / hour for the first 4 hours and 10 ° C / hour for an additional 4 hours. To facilitate crystallization, about 1 gram (about 1 weight percent) of technical N- [2,4-dichloro-5- [4- (difluoromethyl) 4,5] was added to the reaction mixture during the eight hour cooling time at 70-75 ° C. -dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl] phenylmethanesulfonamide. After cooling the reaction mixture to room temperature, it was transferred to an aqueous centrifuge, where it was centrifuged for 30 minutes to remove the mother liquor. The obtained filter cake was washed three times. 5 liters of cold toluene added directly to the centrifuge. The mixture was centrifuged for 30 minutes to remove the toluene wash solution, the filter cake was removed from the centrifuge, and dried at 65 ° C and 4 kilopascals (30 mm Hg) for 4 hours. 108.99 g (85 percent) of N- [2,4-dichloro-5- [4- (difluoro-40-methyl) -4,5-dihydro-3-methyl-5-oxo-1H-2,4,4-triazole 11] were obtained. -yl] phenylmethanesulfonamide.

Example 3

In this example, a process for preparing N- [2,4-dichloro-5- [4- (difluoromethyl) -4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole-1] is described. -yl] phenyl] methanesulfonamide using 1,1,3,3-tetramethylurea as a catalyst.

A solution of 20.0 grams (0.054 mol - 1.0 equivalent) of 1- (5-amino-2,4-dichlorophenyl) -4,5-dihydro-450 difluoromethyl-3-methyl-1,2,4-triazole-5 (1H) -one having a purity of 83.1 percent, 9.2 grams (0.08 moles of 1.5 equivalents) of methanesulfonyl chloride, 0.17 grams (0.001 moles - 0.03 equivalents) of 1,1,3,3-tetramethylurea and 17 grams of xylene (an excess weight of triazole relative to the solvent of 18 percent) was heated to 141-144 ° C under nitrogen atmosphere with stirring for 6 hours. After this time, analysis by gas chromatography (GC) of pro-6C303112B6 showed that 1.2 percent of the original 1,2,4-triazol5 (1H) -one starting material remained in the reaction mixture.

Example 4

This example describes a process for preparing N - [2,4-dichloro-5- [4- (difluoromethyl) -4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole-1- yl] phenyl] methanesulfonamide using DMF as a catalyst.

A solution of 20.0 grams (0.054 mol - 1.0 equivalent) of 1- (5-amino-2,4-dichlorophenyl) -4,5-dihydro-4-difluoromethyl-3-methyl-1,2,4-triazole-5 ( 1 H) -one having a purity of 83.1 percent, 17 grams of xylene (the excess weight of triazole relative to the solvent was 18 percent), 9.2 grams (0.08 mol 1.5 equivalents) of methanesulfonyl chloride and 0.17 grams (0.002 mol - 0.04 equivalents) DMF was heated to 140 ° C under nitrogen for 4 hours with stirring. After this time, gas chromatography (GC) analysis showed that 99.4 percent of the initial 1,2,4-triazol-5 (1H) -one had been converted. The reaction mixture was cooled to 23 ° C and stored for later use.

Example 5

In this example, a process for preparing N- [2,4-dichloro-5- [4- (difluoromethyl) -4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole] is described. -1-yl] phenyl] methanesulfonamide using DMAC as a catalyst.

In a 500 ml round bottom flask equipped with a mechanical stirrer and thermometer was charged 20.0 grams (0.05 mol - 1.0 equivalent) of 1- (5-amino-2,4-dichlorophenyl) -4,5-dihydro-4-ol. - difluoromethyl-3-methyl-1,2,4-triazol-5 (1H) -one having a purity of 79.0 percent, 0.2 g (0.002 mol - 0.04 equivalents) of DMAC, 19.0 g (0, 16 mol - 3.2 equivalents) of methanesulfonyl chloride and 19.0 grams of toluene (5 weight percent triazole relative to the solvent). After all components were added, the resulting reaction mixture was heated to 119-120 ° C and stirred at this temperature for about 6.75 hours. After this time, gas chromatography (GC) analysis showed complete conversion of the starting 1,2,4-triazol-5 (1H) -one.

Example 6

This example describes a process for preparing N- [2,4-dichloro-5- [4- (difluoromethyl) -4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole] - 1-yl] phenylmethanesulfonamide using HMPA as a catalyst.

A solution of 10.0 grams (0.029 mol - 1.0 equivalent) of 1- (5-amino-2,4-dichlorophenyl) -4,5-dihydro-4-difluoromethyl-3-methyl-1,2,4-triazole-5 (1H -one having a purity of 88.7 percent, 8.9 grams of xylene (the excess weight of triazole relative to the solvent was 12 percent), 4.9 grams (0.043 mol 1.5 equivalents) of methanesulfonyl chloride, and 0.1 grams (0.0006 mol) 0.02 equivalents) HMPA was heated to 148 ° C under nitrogen for 4.5 hours with stirring. After this time, gas chromatography (GC) analysis showed 98% of the initial 1,2,4-triazol-5 (1H) -one to be converted.

-7GB 303112 Β6

Example 7

In this example, a method for preparing N- [2,4-dichloro-5- [4- (difluoromethyl) -4,5-dihydro-3-methyl-5-oxo-1 H -1,2,4-triazo-1-1] is described. -yl] phenyl] methanesulfonamide using 5-N-acetyl as catalyst.

In a 50 ml round bottom flask equipped with a mechanical stirrer and thermometer was charged 20.0 grams (0.065 mol - 1.0 equivalent) of 1- (5-amino-2,4-dichlorophenyl) -4,5-dihydro-4-difluoromethyl-3- methyl-1,2,4-triazol-5 (1H) -one, 19.0 grams of xylene (5 weight percent triazole relative to the solvent), 11.0 grams (0.096 mol - 1.5 equivalents) of methanesulfonyl chloride and 1 1.6 g (0.005 mol - 0.08 equivalents) of 5-N-acetyl. After all the components had been added, the resulting reaction mixture was heated to 145 ° C and stirred at this temperature for approximately 4.67 hours. After this time, gas chromatography (GC) analysis showed complete conversion of 99.6 percent of the total starting 1,2,4-triazol-5 (1H) -one.

Example 8

This example describes a method for preparing N- [2,4-dichloro-5- [4- (difluoromethyl) -4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-i-yl] Phenyl] methanesulfonamide using DMF as a catalyst on a pilot scale (in a reactor of approximately 190 liters (i.e. 50 gallons)).

A glass-lined reactor of approximately 190 liters (i.e. 50 gallons) was charged with 118.9 kg (262 lbs) of 1- (5-amino-2,4-dichlorophenyl) -4,5-dihydro-4 solution under nitrogen. - 16 weight percent difluoromethyl-3-methyl-1,2,4-triazol-5 (1H) -one. The solution was heated to about 105-115 ° C with stirring. During heating, the nitrogen inlet was removed and the reaction vessel was tightly sealed at a pressure of approximately 100 to 104 kilopascals (i.e. approximately 750 to 780 mm Hg). Upon reaching the above temperature, toluene was removed from the reaction mixture at such a rate that the temperature of the mixture was maintained at about 110-120 ° C and the reactor pressure was 100-104 kilopascals (i.e. 750-780 mm Hg). wherein the amount of toluene removed was such as to obtain 35.38 kg (78 pounds) of a 1- (5-amino-2,4-dichlorophenyl) -4,5-dihydro-4-difluoromethyl-3-methyl-1,2 solution. 4'-triazol-5 (1 H) -one in toluene at 50 weight percent (i.e., this solution contained 17.69 kg (57.4 mol - 1.0 equivalent) of triazole). The reaction vessel was cooled to a temperature in the range of about 85 to 92 ° C and 168 grams (0.37 lbs) (2.28 mol 0.04 equivalents) of DMF was added thereto. To the reaction mixture was added 10.75 kg (i.e. 23.7 pounds) (94.3 moles - 1.64 equivalents) of methanesulfonyl chloride at such a rate that the temperature of the reaction mixture remained between 85 and 92 ° C. Thereafter, the temperature of the reaction mixture was slowly increased to 140-145 ° C, maintaining the pressure in the reaction vessel in the range of 96.5 kilopascals to 117.2 kilopascal (i.e., 14 to 17 psig), and thus the heating rate of the reaction mixture was approximately 5 ° C per hour. While the mixture was heated to 140-145 ° C, all the hydrogen chloride evolved was discharged from the reactor. Subsequently, the reaction mixture was stirred at 140-145 ° C for 8 hours. During the eight hour heating, the reaction mixture was analyzed by gas chromatography (GC) to determine the degree of conversion of the starting compound to the product. After heating the mixture for 8 hours, 99% conversion of the starting compound to the product was achieved, which was an acceptable result. The reaction vessel was cooled to about 83-87 ° C and the pressure in the vessel was reduced to atmospheric over 15 minutes. After pressure equalization, 104 kg (230 lb) of fresh toluene was added to the reaction vessel. The resulting solution was stirred for 30 minutes and then transferred to a second glass-lined reactor of approximately 190 liters (i.e. 50 gallons), which was pre-filled with 125 to 129 kilograms (275 to 285 pounds) of water and preheated to 80 to 82 ° C. The resulting mixture was stirred at 80-83 ° C for 25-35 minutes and then allowed to sit for approximately 25-35 minutes. The organic layer was separated from aqueous and an additional 125-139 kg (275-285 pounds) of water was added. After repeating the process of mixing the mixture followed by settling, the organic layer was first separated from the aqueous layer and subsequently cooled to 20 ° C over 8 hours, with a cooling rate of 5 ° C / hour and 10 ° C / hour during the first four hours. the remaining four hours. To facilitate crystallization, about 0.23 kg (about 0.5 lbs) of N - [2,4-dichloro-5- [4- (difluoromethyl) D 4] was added to the reaction mixture during the eight hour cooling time at 70-75 ° C. 5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl] phenyl] methanesulfonamide After cooling the reaction mixture to room temperature, it was transferred to a suitable centrifuge for 30 minutes The separated mother liquor was returned to the reaction vessel, where it was stirred for 10 minutes to remove the remaining product, and then the mother liquor was transferred to a centrifuge, where it was centrifuged as described above. kilograms (50 pounds) of fresh toluene introduced directly into the centrifuge, and the mixture was centrifuged for 30 minutes to remove the toluene wash solution. The mother liquor and toluene wash solution were combined to isolate the dissolved product, the filter cake was removed from the centrifuge and dried at 80 ° C and 4 kilopascals (30 mm Hg) for 8 hours. 24.9 kg (55 pounds) of N- [2,4-dichloro-5- [4- (difluoromethyl) -4,5-dihydro-3-methyl-5-oxo-1H-1,2,4- triazol-1-yl] phenyl] methanesulfonamide.

Example 9

This example describes a process for the preparation of N- [2-chloro-4-fluoro-5- [1-methyl-6-trifluoromethyl-2,4- (1H, 3H) -pyrimidindion-3-yl] phenyl] methanesulfonamide with using NMP as a catalyst.

To a stirred solution of 37.5 grams (0.1 mol - 1.0 equivalent) of 3- (5-amino-4-chloro-2-fluorophenyl) -1-methyl-6-trifluoromethyl-2,5- (1H, 3H) 1-pyrimidinedione in 37.5 grams of xylene was gradually added 17.4 grams (0.15 mol - 1.5 equivalents) of methanesulfonyl chloride and 0.1 7 grams (0.002 mol - 0.4 equivalents) of NMP. After all the components had been added, the resulting reaction mixture was heated to about 115 ° C for 6 hours.

Although the present invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to those skilled in both organic chemistry that many changes and modifications can be made to the above description without departing from the scope of the present invention.

Claims (17)

PATENT CLAIMS A process for the preparation of sulfonamides of formula II (II) comprising at least reacting an aniline of formula I with sulfonating agent A of formula R'-SO ₂ -Z at a temperature in the range of from 30 to 160 ° C, namely in the presence of a catalytic amount of either (i) amide B-1 or (ii) a tertiary amine B-2 boiling at atmospheric pressure above 140 ° C, provided that when amide B-1 is N, Nd or methyl For forms Id, the reaction is carried out at a temperature ranging from 120 to 160 ° C, wherein the groups X and Y in both formulas 1 and II and Z are independently selected from the group consisting of hydrogen, halogen, C _1-20 alkyl, C _{(_ 20} haloalkyl, amino, nitro, C _"20 alkoxy group, a hydroxyl group, an anhydride group, C _t _ ₂₀ alkylthio, C _{5] 0} arylthio, C ₅ _ | ₀ aryloxy, C | _ ₂₀ alkylsulfonyl, C ₅ , ₀ arylsulfonyl group and substituted or unsubstituted C _5-10 aryl group, wherein said C _5-10 aryl group may be substituted by one or more substituents selected from the group consisting of halogen, C 1-20 alkyl, C _1-20 alkoxy, nitro, amino, amido C | _2O alkylthio, C ₅ _i ₀ aryl, _C .io arylthio, C-io aryloxy group, a C | _ ₂ of C5_io alkylsulfonyl and arylsulfonyl; R in both formulas I and II is independently selected from the group consisting of hydrogen, C ₂₀ alkyl, C | _ ₂₀ haloalkyl groups, _{C) 0} aryloxy, substituted or unsubstituted Cs-io aryl, and substituted or unsubstituted 5 to 10-membered heterocyclyl group containing from 1 to 4 atoms selected from nitrogen, sulfur and oxygen, said C _5-6 alkylsulfonyl group; _The aryl or 5- to 10-membered heterocyclyl group may be substituted by one or more substituents selected from the group consisting of halogen, C _1-20 alkyl, C _1-20 alkoxy, nitro, amino, amido, C _1-2 alkylthio, C _5-10 | ₀ aryl, _C5 _io 10GB 303112 B6 arylthio group, a C ₅ _ ₁₀ aryloxy group, C 1-20 alkylsulfonyl, and C ₅ _i ₀ arylsulfonyl; and R ¹ is selected from the group consisting of hydrogen, C _'2 alkyl groups, C'i? o halo5 alkyl and C ₅ _io aryl group. 2. A process according to claim 1 wherein both X and Y are halogen atoms. io 3. The process of claim 1 wherein X is 2-chloro or 2-fluoro and Y is 4-chloro. The process of claim 1 wherein R is a substituted or unsubstituted 5- to 10-membered heterocyclyl group containing from 1 to 4 15 heteroatoms selected from nitrogen, sulfur and oxygen, which may be substituted with one or more substituents selected from the group consisting of halogen, C _1-2 alkyl, C 1-20 alkoxy, nitro, amino, amido, C _1-20 alkylthio, C _S-IO aryloxy, _C5 _] ₀ aryl, _{C5 _] o} arylthio, C | _ ₂₀ alkylsulfonyl and C ₅ _i ₀ Isulfony Íovou aryl group. 5. The process of claim 4 wherein R is 4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl, 1- methyl-6-trifluoromethyl-2,4,4- (1H, 3H) -pyrimidinedione-3-yl or 1-amino-6-trifluoromethyl 12,4- (1H, 3H) -pyrimidinedione-3 -yl group. 6. The method according to claim 1, characterized in that R ¹ is aryl or alkyl, and Z is a halogen atom or a group anhydridylová. 7. The method according to claim 6, characterized in that R ¹ is methyl And Z is a chlorine atom. The process of claim 1 wherein X is 2-chloro; Y is 4-chloro; R is 4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-2,4,4-triazolyl; and R ¹ 35 represents a methyl group. The process of claim 1 wherein the amide B1 and amine B-2 are selected from the group consisting of 1-methyl-2-pyrrolidinone, 1,1,3,3-tetramethylurea, N, N-dimethylacetamide, hexamethylphosphoramide, isoquinoline and 1- (2,4-dichloro-5-acetamido-phenyl) -4-difluoro-40-methyl-5-dihydro-3-methyl-1H-2,4,4-triazol-5-one. 10. The process of claim 1 wherein said reaction is carried out in a solvent. 45 11. The process of claim 10 wherein said solvent is an aromatic, alkane or alkene solvent. 12. The process of claim 11 wherein said solvent is selected from the group consisting of toluene, xylene, and diethylbenzene. 13. The process of claim 12 wherein said solvent is toluene. 14. The process of claim 1 wherein said reaction mixture is maintained for a period of time 55 was heated to 110-160 ° C for 3-12 hours. - 11 GB 303112 B6 The process of claim 14, wherein said reaction mixture is heated to a temperature of from 120 to 150 ° C for a period of from 3 to 7 hours. 16. A process according to claim 1, wherein from 1 molar equivalent to 5 molar equivalents of sulfonating agent A is used, based on the amount of aniline of formula I. 17. The method of claim 16, wherein from 1.3 molar equivalents to 4 molar equivalents of sulfonating agent A is used, based on the amount of aniline of formula (I).